Galectin 3-binding protein (LGALS3BP) depletion attenuates hepatic fibrosis by reducing transforming growth factor-β1 (TGF-β1) availability and inhibits hepatocarcinogenesis

  • Cancer Commun (Lond). 2024 Jul 28. doi: 10.1002/cac2.12600.
Dae-Hwan Kim  1  2  3  4 ,  Minjeong Sung  1  2  3  4  5 ,  Myong-Suk Park  1  2  3  4 ,  Eun-Gene Sun  1  2  4 ,  Sumin Yoon  6 ,  Kyung Hyun Yoo  6 ,  Kamalakannan Radhakrishnan  7 ,  Sung Yun Jung  8 ,  Woo-Kyun Bae  1  2  3  4  5 ,  Sang-Hee Cho  1  2  3  4 ,  Ik-Joo Chung  1  2  3  4
Affiliations
  • 1. Department of Internal Medicine, Division of Hematology and Oncology, Chonnam National University Medical School, Hwasun, South Korea.
  • 2. Department of Internal Medicine, Division of Hematology and Oncology, Chonnam National University Hwasun Hospital, Hwasun, South Korea.
  • 3. Combinatorial Tumor Immunotherapy MRC Center, Chonnam National University Medical School, Hwasun, South Korea.
  • 4. National Immunotherapy Innovation Center, Hwasun, South Korea.
  • 5. BioMedical Sciences Graduate Program, Chonnam National University, Hwasun, South Korea.
  • 6. Department of Biological Science, Sookmyung Women's University, Seoul, South Korea.
  • 7. Clinical Vaccine R&D Center, Chonnam National University, Hwasun, South Korea.
  • 8. Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas, USA.
PMID: 39073023 DOI: 10.1002/cac2.12600
Abstract

Background: Increased Galectin 3-binding protein (LGALS3BP) serum levels have been used to assess hepatic fibrosis stages and the severity of hepatocellular carcinoma (HCC). Considering the crucial role of transforming growth factor-β1 (TGF-β1) in the emergence of these diseases, the present study tested the hypothesis that LGALS3BP regulates the TGF-β1 signaling pathway.

Methods: The expression levels of LGALS3BP and TGFB1 were analyzed in patients with metabolic dysfunction-associated steatohepatitis (MASH) and HCC. Multiple omics techniques, such as RNA-sequencing, transposase-accessible chromatin-sequencing assay, and liquid chromatography-tandem mass spectrometry proteomics, were used to identify the regulatory mechanisms for the LGALS3BP-TGF-β1 axis. The effects of altered TGF-β1 signaling by LGALS3BP were investigated in conditional LGALS3BP-knockin and LGALS3BP-knockout mice.

Results: In patients with MASH and HCC, the levels of LGALS3BP and TGFB1 exhibited positive correlations. Stimulation of LGALS3BP by the inflammatory cytokine interferon α in HCC cells or ectopic overexpression of LGALS3BP in hepatocytes promoted the expression levels of TGFB1. Aggravated fibrosis was observed in the livers of hepatocyte-specific LGALS3BP-knockin mice, with increased TGFB1 levels. LGALS3BP directly bound to and assembled Integrin αV, an integral mediator required for releasing active TGF-β1 from extracellular latent complex with the rearranged F-actin Cytoskeleton. The released TGF-β1 activated JunB transcription factor, which in turn promoted the TGF-β1 positive feedback loop. LGALS3BP deletion in the hepatocytes downregulated TGF-β1 signaling and CCl4 induced fibrosis. Moreover, LGALS3BP depletion hindered hepatocarcinogenesis by limiting the availability of fibrogenic TGF-β1.

Conclusion: LGALS3BP plays a crucial role in hepatic fibrosis and carcinogenesis by controlling the TGF-β1 signaling pathway, making it a promising therapeutic target in TGF-β1-related diseases.

Keywords
FAK; F‐actin; Integrin αV; Interferon α; JunB; LGALS3BP; TGF‐β1; hepatic carcinogenesis; metabolic dysfuntion‐associated steatohepatitis; tensile force.
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